The role of cellular senescence in bone loss and recovery in periodontal disease

细胞衰老在牙周病骨质流失和恢复中的作用

• 批准号: 10741898
• 负责人: Mizuho Kittaka
• 金额: $ 15.85万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741898
• 关键词: Address; Adult; Adverse effects; Age; Age-Related Bone Loss; Aging; Alveolar Bone Loss; Attenuated; Biological; Biological Assay; Biology; Bone Resorption; Cell Aging; Cells; Clinical Trials; Development; Disease; Disease model; Excision; Foundations; Future; Genes; Gingiva; Goals; Human; Immunohistochemistry; Induction of Apoptosis; Inflammation; Life; Ligature; Mandible; Mature Bone; Measurement; Mechanics; Mediator; Mus; Musculoskeletal; Osteoclasts; Osteogenesis; Outcome; Outcome Study; Pathologic; Pathology; Patients; Periodontal Diseases; Periodontal Ligament; Pharmaceutical Preparations; Phenotype; Play; Predisposition; Prevalence; Prevention strategy; Public Health; Recovery; Role; Testing; Therapeutic Intervention; Tissues; Tooth Cervix; Tooth Loss; Tooth structure; Work; age related; alternative treatment; alveolar bone; bone; bone loss; clinical efficacy; conventional therapy; experimental study; fisetin; improved; novel therapeutics; phenotypic biomarker; prevent; senescence; stressor; telomere; therapeutically effective; treatment strategy

Project Summary/Abstract The prevalence of tooth-supporting alveolar bone loss by periodontal disease (PD) steeply rises in the 3rd and 4th decades of life. As such, PD is a leading cause of tooth loss in adults. Mechanisms behind the increased susceptibility to PD bone loss in adulthood are unknown. 17 to 23% of PD patients do not respond to current treatment and thus progress to tooth loss. Our long-term goal is to identify the mechanism of age-related bone loss in PD to develop mechanistically based therapies of PD bone loss. A potential factor in the development of PD bone loss is the accumulation of senescent cells. Senescent cell accumulation in tissues is increasingly recognized as a driver of age-associated disorders. To mitigate the deleterious effects, senescent cells can be removed by drugs called senolytics that selectively induce apoptosis in senescent cells. Fisetin is a recently characterized senolytic without observable adverse effects and is being evaluated in clinical trials targeting pathological conditions hallmarked by senescent cell burden. Our preliminary studies using the ligature-induced PD (LIP) model showed that LIP induces initial rapid bone resorption followed by a rapid recovery due to bone formation by day 14 in young mice (2.5 months). In contrast, significant bone loss remained at day 14 in mature mice (8-12 months). Also, mature mice showed greater bone volume loss compared to young mice, indicating the increased susceptibility to LIP-induced bone loss in mature mice. Furthermore, bone formation rate in mature mice with LIP was lower than young mice, suggesting that diminished bone formation rate is responsible for the increased susceptibility to LIP-induced bone loss in mature mice. We found increases in expression levels of senescence marker genes in periodontal tissue of mature mice before PD induction, suggesting that accumulation of senescent cells in the tissue increase the susceptibility to LIP-induced bone loss in mature mice. Our hypothesis is that accumulation of the senescent cells is a critical factor responsible for inhibiting bone recovery and for increasing bone loss susceptibility in the pathology of PD bone loss, and that senolytic treatment will improves the PD-driven bone loss. Here, we propose the following aims: Specific Aim 1: Determine if the clearance of pre-existing senescent cells by the senolytic, fisetin, will prevent PD alveolar bone loss. 12-month-old mice will be pre- treated with fisetin to clear and prevent age-related senescent accumulation before inducing LIP, and we will analyze the effect of senescent cell clearance by fisetin pre-treatment on LIP-induced bone loss. Specific Aim 2: Determine if fisetin treatment will induce recovery from PD-induced bone loss. We will induce LIP in 12- months-old mice and wait until bone resorption progress to detectable levels before starting fisetin treatment. We will then analyze bone loss induced by LIP. Our team is uniquely suited to conduct these experiments with expertise in periodontology, bone biology, and cellular senescence in musculoskeletal tissue. Outcomes from this work will lead us to further mechanistic studies of the role of senescence in PD toward our long-term goal.

项目总结/摘要 牙周病（PD）引起的牙槽骨缺损的患病率在第三年急剧上升， 4th十年的生活因此，PD是成年人牙齿脱落的主要原因。增长背后的机制 成年期PD骨丢失的易感性尚不清楚。17 - 23%的PD患者对当前治疗无反应 治疗，从而导致牙齿脱落。我们的长期目标是确定与年龄相关的骨骼的机制 PD的骨丢失，以开发基于机制的PD骨丢失疗法。发展的一个潜在因素 PD骨丢失的主要原因是衰老细胞的积累。衰老细胞在组织中的积累越来越多 被认为是与年龄相关的疾病的驱动因素。为了减轻有害影响，可以将衰老细胞 被称为senolytics的药物清除，这种药物选择性地诱导衰老细胞的凋亡。非瑟酮是最近 特征性的衰老清除剂没有可观察到的不良反应，正在临床试验中进行评估， 以衰老细胞负荷为特征的病理状况。 我们使用结扎诱导的PD（LIP）模型的初步研究表明，LIP诱导了最初的快速PD， 骨吸收，随后由于在年轻小鼠（2.5个月）中骨形成而在第14天快速恢复。在 相比之下，在成熟小鼠（8 - 12个月）中，在第14天仍然存在显著的骨丢失。此外，成熟的小鼠显示， 与年轻小鼠相比，更大的骨体积损失，表明对LPS诱导的骨的易感性增加 成熟小鼠的损失。此外，LIP成熟小鼠的骨形成率低于年轻小鼠， 这表明骨形成率降低是导致对LPS诱导的骨形成的易感性增加的原因。 成年小鼠的骨丢失。我们发现牙周组织中衰老标记基因的表达水平增加， 在PD诱导前成熟小鼠的组织中，提示衰老细胞在组织中的积累 增加成熟小鼠对脂多糖诱导的骨丢失的易感性。我们的假设是 衰老细胞是负责抑制骨恢复和增加骨损失的关键因素 PD骨丢失的病理学易感性，以及衰老清除治疗将改善PD驱动的骨 损失具体目标1：确定是否清除预先存在的 衰老细胞的senolytic，非瑟酮，将防止PD牙槽骨丢失。12个月大的小鼠将在 在诱导LIP之前用非瑟酮治疗以清除和防止与年龄相关的衰老积累，我们将 分析非瑟酮预处理对衰老细胞的清除作用对脂多糖诱导的骨丢失的影响。具体目标 2：确定非瑟酮治疗是否会诱导PD诱导的骨丢失恢复。我们将在12分钟内诱导LIP- 月大的小鼠，并等待直到骨吸收进展到可检测的水平，然后开始非瑟酮治疗。 然后我们将分析LIP引起的骨丢失。我们的团队非常适合进行这些实验， 牙周病学、骨生物学和肌肉骨骼组织细胞衰老方面的专业知识。的成果 这项工作将引导我们对衰老在PD中的作用进行进一步的机制研究，以实现我们的长期目标。